Precision genome editing has become a reality with the discovery of base editors. Cytosine base editor (CBE) technologies are improving rapidly but are mostly optimized for TC dinucleotide targets. Here, we report the development and implementation of APOBEC Reporter Systems for Evaluating diNucleotide Editing Levels (ARSENEL) in living cells. The ARSENEL panel is comprised of four constructs that quantitatively report editing of each of the four dinucleotide motifs (AC/CC/GC/TC) through real-time accumulation of eGFP fluorescence. Editing rates of APOBEC3Bctd and AIDΔC CBEs reflect established mechanistic preferences with intrinsic biases to TC and GC, respectively. Twelve different (new and established) base editors are tested here using this system with a full-length APOBEC3B CBE showing the greatest on-target TC specificity and an APOBEC3A construct showing the highest editing efficiency. In addition, ARSENEL enables real-time assessment of natural and synthetic APOBEC inhibitors with the most potent to-date being the large subunit of the Epstein-Barr virus ribonucleotide reductase. These reporters have the potential to play important roles in research and development as precision genome engineering technologies progress toward achieving maximal specificity and efficiency.

01 Nov 2017·Oral OncologyQ2 · MEDICINE

Multi-modality analysis supports APOBEC as a major source of mutations in head and neck squamous cell carcinoma

Q2 · MEDICINE

Article

Author: Thomas, Sean ; Agrawal, Nishant ; Faden, Daniel L ; DeRisi, Joseph ; Cantalupo, Paul G ; Myers, Jeffrey

OBJECTIVESThe mutagenic processes underlying head and neck squamous cell carcinoma (HNSCC) are poorly understood. Pan-cancer mutational signature analyses have identified a signature for APOBEC, a cytosine deaminase, in a subset of cancers, including HNSCC. The role of APOBEC activity in HNSCC remains poorly understood. Therefore, we sought to determine the role of APOBEC in HNSCC pathogenesis.MATERIAL AND METHODSUtilizing bioinformatic approaches we explored the role of APOBEC mediated mutations in tumor exomes, transcriptomes and germline exomes from 511HNSCC patients in the TCGA.RESULTS58% of HNSCC were statistically enriched for the APOBEC signature. APOBEC3A expression had the highest correlation coefficient with APOBEC mutation rate. Gene specific motif analysis revealed a slight predominance of APOBEC3A mutations. Canonical pathway analysis demonstrated immune pathway upregulation in APOBEC mutation rich samples. Overall mutational burden was positively correlated with APOBEC enrichment.CONCLUSIONSAPOBEC mediated mutations are highly prevalent in HNSCC. APOBEC3A is the most likely gene to be active in HPV+ HNSCC. APOBEC activity correlates with upregulation of immune signaling pathways, supporting the hypothesis that APOBEC activity could be activated as part of the innate immune response.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	OyaGen, Inc.	05 Oct 2021

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